A combined genetic analysis of Hyperparathyroidism-jaw tumor syndrome (HPT-JT) clinical resources from seven institutions has refined the genetic locus to a 5cM region at 1q31 flanked by D1S238 and D1S2794 by recombination mapping. Using the publicly available high throughput draft human genome sequence, we have identified and are currently in the process of characterizing a total of 56 potential candidate genes which map within the HPT-JT critical interval. We are characterizing these candidate genes for tissue distribution and transcript length by Northern analysis. All partial transcripts are currently being extended into full-length cDNAs using both Genetrapper and RACE methodologies. Candidate genes have been prioritized for mutation analysis based upon expression pattern and available functional information. Mutation screening is being carried out on patient genomic DNA using direct sequencing of exons utilizing the Applied Biosystems DNA Fluorescent Capillary Sequencer. Candidate genes are being screened in hopes of identifying disease associated mutations in HPT-JT patient DNA samples. We have recently identified a series of inactivating mutations in a gene of unknown function, suggesting that we have identified a novel tumor suppressor gene which causes HPT-JT. A manuscript has been recently submitted and currently in review. We are currently performing experiments to better understand the function of the protein encoded by the gene through the development of a knockout mouse model. We are also working with other investigators to determine the frequency of mutations in this gene in sporadic parathyroid and renal tumors. The identification of the HPT-JT gene could lead to early diagnosis and the identification of novel therapies for this disease. The identification of this gene could also shed light on potentially novel and important endocrine related pathways.